Approximately 65% of all prescription drugs are manufactured as solid dosage forms, which include tablets and capsules. In both cases the final formulation consists of a carrier (or mixtures of carriers) and an active pharmaceutical ingredient (“API”) which is homogeneously distributed throughout the carrier. For very potent drugs the amount of API in the solid dosage form can be as low as 0.1% by weight. This very low API loading poses one of the biggest problems in pharmaceutical product development: the control of blend uniformity. Low API content variability in the blend or high blend homogeneity are highly desired and strictly enforced by the U.S. Food and Drug Administration (“FDA”). Current guidelines developed by the FDA require API content variability in finished drug products to have relative standard deviation (“RSD”) of no higher than 6%, with lower being better. In the commonly available approaches for blend uniformity control (for example, direct blending, wet or dry granulation) as the API concentration decreases, the variability of the blend increases; this makes it very difficult to meet FDA's requirements for low drug loadings. Therefore a process or method that is able to tightly control API variability in blends, regardless of drug loadings, has become very desirable.
Another important aspect of pharmaceutical process development is the final cost. As pharmaceutical companies strive to develop cheaper and more affordable drugs, any possible elimination of lengthy and expensive unit operations will become commercially advantageous. One group of such unit operations is associated with the control of API attributes (size, size distribution, shape, crystal form, bulk density, etc.). These unit operations can include crystallization and various milling and de-lumping steps. The need for control of API attributes is solely dictated by the drug product development and usually is associated with improvements in blend uniformity, drug release profile, and physical stability of the finished product. Having a formulation process that can make these and other steps unnecessary will provide a large advantage to pharmaceutical companies and the industry as a whole.
In addition to cost savings in the manufacturing process, a very important part in the overall economics is the cost associated with research and development efforts. Currently, to at least some degree, these research investments are driven by the difficulty of the particular drug formulation. This generally is true for new molecules, where processing difficulties can cause delays in launching the product, and for generic products, where difficulties in developing a suitable formulation often are the paramount factor controlling successful development. These difficulties can be associated with the API properties (difficult to control crystal form, low bulk density, cohesive powders, difficult to achieve particle size distribution (“PSD”), etc.) or with the drug product properties (low blend uniformity, inconsistent release profile, poor powder flow, etc.). There is interest in having a robust manufacturing process that can be applied to a number of products regardless of the individual API properties and specifics. One area that can greatly benefit from such a robust manufacturing platform is the preparation of clinical supplies, whether for early phase studies for new molecules, or for bioequivalence studies for generic versions of existing products. The uncertainty of the drug's future at that stage makes such a platform extremely cost effective and highly desirable for pharmaceutical companies.
The described invention addresses these problems. The described invention provides a method for impregnating a drug solution throughout the volume of a porous carrier by spraying the solution onto the carrier in a fluid bed processor, generating a composite particle in which API bulk properties are no longer important.